Vasopressin (AVP) antagonists represent a novel therapeutic class for the treatment of depression. The potential utility of these compounds has emerged from observations in depressed individuals, findings in animal models, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. This Fast Track proposal seeks support for the identification of novel mixed vasopressin 1a/1b (V1a/V1b) receptor antagonists and the preclinical development of recently discovered molecules in this class that already demonstrate excellent biological activity in vitro. The scientific basis for mixed V1a/V1b antagonists as a pharmacotherapy for depression includes: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of depression, 2) recognition that AVP, not CRF, drives HPA function associated with chronic psychological stress, and 3) the localization of V1a and V1b receptors in regions involved in the control of social behaviors and HPA axis regulation (V1a in limbic system; V1b in limbic system and anterior pituitary). The initial development of these mixed antagonists to date has been supported by private sector venture funding. SBIR Fast Track support will enable essential preclinical development work that will advance candidate molecules to the stage where bulk synthesis and IND-enabling toxicology can be undertaken. Bringing candidates to this status will accelerate commercialization opportunities by significantly enhancing the likelihood of additional private financial investment or a co-development partnership structure with a major pharmaceutical house. PUBLIC HEALTH RELEVANCE: The public health need for new pharmaceutical treatments for depression is well documented. Depression affects some 20 million Americans each year and carries a conservatively estimated annual total economic burden of $125 billion. Existing drugs for depression are not uniformly effective, frequently have undesirable side effects, and do not help some 50% of individuals suffering from the disorder according to recent estimates. These limitations demonstrate that a new treatment approach through mixed V1a/V1b receptor antagonism may offer a significant opportunity for improved outcomes with substantial societal benefit.